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IL-17A upregulates P-glycoprotein expression in peripheral blood lymphocytes of patients with rheumatoid arthritis through TAK1

1, 2, 3, 4, 5, 6, 7, 8, 9, 10

  1. Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China.
  2. Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China.
  3. Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China.
  4. Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China.
  5. Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China.
  6. Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China.
  7. Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China.
  8. Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital/Children's Hospital Boston, Harvard Medical School, Boston, USA.
  9. Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China.
  10. Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China. snwch@sina.com

CER11969 Submission on line
Full Papers

Rheumatology Article

 

Abstract

OBJECTIVES:
P-glycoprotein (P-gp) mediated drug efflux is the most essential mechanism of multi-drug resistance (MDR) in rheumatoid arthritis (RA). The study was undertaken to clarify the mechanism whereby IL-17 regulate the P-gp efflux function in peripheral blood lymphocytes of patients with RA.
METHODS:
Lymphocytes from RA patients and healthy individuals were cultured with IL-17A (0, 10, 100 ng/ml), IL-17A+(5Z)-7-Oxozeaenol (TAK1 inhibitor), and IL-17A+PD98059 (ERK inhibitor), respectively. 24h later, the level of P-gp mRNA expression in peripheral blood lymphocytes was detected by RT-PCR. Meanwhile, the efflux potential of P-gp was assessed by flow cytometry using the fluorescent dye Rhodamine 123, a substrate of P-gp. In order to confirm whether the inhibitors had worked, ERK1/2 and p65, as well as their phosphorylation were detected utilising Western blot analysis.
RESULTS:
With the exception of the expression of P-gp mRNA between control and IL-17A group, the mRNA expression, as well as the function of P-gp in the different group of healthy individuals was similar, and there was no significant difference (p>0.05). However, as for the RA patients, increased expressions of P-gp mRNA and efflux function were detected in IL-17A group compared with control. Moreover, IL-17A upregulated mRNA level and function of P-gp in a concentrate dependent manner. Upregulated expression of P-gp mRNA and efflux potential of P-gp were inhibited by TAK1 or ERK inhibitors in RA peripheral blood lymphocytes. Among them, TAK1 inhibitor, (5Z) -7-Oxozeaenol, showed a significant difference (p<0.05). Also, the decreased phosphorylation levels of ERK1/2 and p65 were detected with PD98059 and (5Z) -7-Oxozeaenol addition, respectively.
CONCLUSIONS:
This study showed that inflammatory cytokines IL-17A can upregulate the mRNA expression level and drug efflux function of P-gp on lymphocytes in RA patients through TAK1, in a concentrate dependent manner, contributing to RA drug resistance. Therefore, this may represent a new target for improving the therapeutic reactivity of DMARDs in the long term for RA patients.

PMID: 31376257 [PubMed]

Received: 05/12/2018 - Accepted : 29/05/2019 - In Press: 19/07/2019